Optimize the interactions at S4 with efficient inhibitors targeting 3C proteinase from enterovirus 71

J Mol Recognit. 2016 Nov;29(11):520-527. doi: 10.1002/jmr.2551. Epub 2016 May 17.

Abstract

Enterovirus 71 (EV71) is the causative agent of hand, foot and mouth disease and can spread its infections to the central nervous and other systems with severe consequences. The replication of EV71 depends on its 3C proteinase (3Cpro ), a significant drug target. By X-ray crystallography and functional assays, the interactions between inhibitors and EV71 3Cpro were evaluated. It was shown that improved interactions at S4 for the substrate binding could significantly enhance the potency. A new series of potent inhibitors with high ligand efficiency was generated for developing antivirals to treat and control the EV71-associated diseases. Copyright © 2016 John Wiley & Sons, Ltd.

Keywords: 3C proteinase; cysteine protease; drug design and development; drug interaction; enterovirus 71; hand, foot and mouth disease.

MeSH terms

  • 3C Viral Proteases
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Cell Line
  • Crystallography, X-Ray
  • Cysteine Endopeptidases / chemistry
  • Cysteine Proteinase Inhibitors / chemical synthesis*
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology
  • Enterovirus A, Human / drug effects
  • Enterovirus A, Human / enzymology*
  • Humans
  • Models, Molecular
  • Structure-Activity Relationship
  • Substrate Specificity
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / chemistry

Substances

  • Antiviral Agents
  • Cysteine Proteinase Inhibitors
  • Viral Proteins
  • Cysteine Endopeptidases
  • 3C Viral Proteases